Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy

Sci Rep. 2019 Jun 21;9(1):9038. doi: 10.1038/s41598-019-44987-6.


Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiomyopathy, Dilated / genetics*
  • Cohort Studies
  • Exome Sequencing
  • Homozygote*
  • Humans
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics*
  • Membrane Proteins / genetics*
  • Middle East
  • Muscle Proteins / genetics*


  • JPH2 protein, human
  • Membrane Proteins
  • Muscle Proteins